Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

Widespread non-joint pain in early rheumatoid arthritis.

Objective: The aim of the study was to assess the development of widespread non-joint pain (WNP) in a cohort of patients with early rheumatoid arthritis (RA), the associated health-related quality of life (HRQoL), and clinical and demographic risk factors for WNP.Method: Incident cases with RA, from the Swedish population-based study Epidemiological Investigation of Rheumatoid Arthritis (EIRA), with a follow-up of at least 3 years, constituted the study population. WNP was defined as pain outside the joints in all four body quadrants and was assessed at the 3 year follow-up. Patients who reported WNP were compared to patients without WNP regarding HRQoL, measured by the Short Form-36, at 3 years, and clinical and demographic characteristics at the time of RA diagnosis.Results: A total of 749 patients constituted the study sample, of whom 25 were excluded after reporting already having severe pain before RA diagnosis. At the 3 year follow-up, 8% of the patients reported having WNP as well as statistically significant worse HRQoL. At the time of RA diagnosis, the patients with WNP had worse pain and pain-related features, while no difference was seen in the inflammatory parameters.Conclusion: WNP occurs in a substantial subset of patients with RA, also early in the course of the disease, and the HRQoL for these patients is significantly reduced. Patients who develop WNP at 3 years are already distinguishable at the time of diagnosis by displaying more pronounced pain ratings together with an average level of inflammatory disease activity.

Social stressors and risk of rheumatoid arthritis and their relationship to known modifiable risk factors: results from the Swedish EIRA study.

Objectives: To investigate whether low social support or low decision latitude at work correlate with risk of rheumatoid arthritis (RA), and whether and how those factors are associated with known modifiable risk factors for RA.Method: The Swedish population-based EIRA study included, from 1996 to 2015, 3724 incident RA cases and 5935 controls, matched for age, gender, and residential area. Participants filled in detailed questionnaires at diagnosis. Using logistic regression, we investigated whether low social support and low decision latitude at work were associated with RA risk, and whether and how these exposures are associated with known modifiable risk factors for RA.Results: Low decision latitude at work was associated with RA risk in unadjusted analyses [odd ratio (OR) = 1.52, 95% confidence interval (CI) = 1.20-1.94], but this association was weakened after adjustment for known RA risk factors (adjusted OR = 1.24, 95% CI = 0.93-1.63). Low social support was not associated with RA risk (unadjusted OR = 1.05, 95% CI = 0.95-1.15). Cases reporting low decision latitude were more often smokers (OR = 2.05, 95% CI = 1.33-3.16), without university degrees (OR = 8.23, 95% CI = 5.13-13.22), and more often female (OR = 2.52, 95% CI = 1.66-3.81), with a similar pattern among controls. Cases reporting low social support were more often men (OR = 1.60, 95% CI = 1.40-1.83), smokers (OR = 1.46, 95% CI = 1.26-1.70), obese (OR = 1.29, 95% CI = 1.09-1.54), physically inactive (OR = 2.78, 95% CI = 1.98-3.90), and without university degrees (OR = 2.04, 95% CI = 1.77-2.36), with a similar pattern among controls.Conclusion: Low decision latitude coexisted with several known environmental/social risk factors for RA, together defining groups of individuals at increased risk of RA. These risk factors should be viewed in context when testing actions to diminish RA risk in prospective studies.

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis.

The current review uses rheumatoid arthritis (RA) as a prominent example for how studies on the interplay between environmental and genetic factors in defined subsets of a disease can be used to formulate aetiological hypotheses that subsequently can be tested for causality using molecular and functional studies. Major discussed findings are that exposures to airways from many different noxious agents including cigarette smoke, silica dust and more interact with major susceptibility genes, mainly HLA-DR genetic variants in triggering antigen-specific immune reactions specific for RA. We also discuss how several other environmental and lifestyle factors, including microbial, neural and metabolic factors, can influence risk for RA in ways that are different in different subsets of RA.The description of these processes in RA provides the best example so far in any immune-mediated disease of how triggering of immunity at one anatomical site in the context of known environmental and genetic factors subsequently can lead to symptoms that precede the classical inflammatory disease symptoms and later contribute also to the classical RA joint inflammation. The findings referred to in the review have led to a change of paradigms for very early therapy and prevention of RA and to efforts towards what we have named 'personalized prevention'. We believe that the progress described here for RA will be of relevance for research and practice also in other immune-mediated diseases.

Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA. METHOD: From two population-based case-control studies, the Scandinavian Lymphoma Etiology (SCALE) study and the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) I study, we identified lymphoma cases with a validated RA diagnosis (n = 50), to whom we matched study participants with RA but no lymphoma (n = 261), lymphoma but no RA (n = 257), and neither RA nor lymphoma (n = 233). Lymphomas were classified according to the WHO classification. Blood samples were analysed for immunoglobulin G (IgG), IgM, and IgA isotypes and IgG1-4 subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression. RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA. CONCLUSION: In this study, neither anti-CCP antibodies (IgG, IgG1-4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA.

VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis.

Rheumatoid arthritis (RA) patients can be stratified into two subgroups defined by the presence or absence of antibodies against citrullinated circular peptides (anti-CCP) with most of the genetic association found in anti-CCP positive RA. Here we addressed the role of VAV1, previously associated to multiple sclerosis (MS), in the pathogenesis of RA in experimental models and in a genetic association study. Experimental arthritis triggered by pristane or collagen type II was induced in DA rats and in the DA.BN-R25 congenic line that carries a polymorphism in Vav1. Difference in arthritis severity was observed only after immunization with pristane. In a case-control study, 34 SNPs from VAV1 locus were analyzed by Immunochip genotyping in 11475 RA patients (7573 anti-CCP positive and 3902 negative) and 15,870 controls in six cohorts of European Caucasians. A combination of the previous MS-associated haplotype and two additional SNPs was associated with anti-CCP negative RA (alleles G-G-A-A of rs682626-rs2546133-rs2617822-rs12979659, OR=1.13, P=1.27 × 10-5). The same markers also contributed to activity of RA at baseline with the strongest association in the anti-CCP negative group for the rs682626-rs12979659 G-A haplotype (ß=-0.283, P=0.0048). Our study suggests a role for VAV1 and T-cell signaling in the pathology of anti-CCP-negative RA.

An in vivo cross-linkable hyaluronan gel with inherent anti-inflammatory properties reduces OA cartilage destruction in female mice subjected to cruciate ligament transection.

OBJECTIVE: To explore the possibility of cartilage protection in osteoarthritis (OA) by intraarticular injection of a chemically modified hyaluronan (HA) gel and investigate whether the chemical modifications provide intrinsic anti-inflammatory activity. METHOD: OA was induced in C57BL/6 mice by anterior cruciate ligament transection (ACLT) and HA gel or carbazate-modified component was injected intra-articularly. Assessment of cartilage rescue was performed by histology, immunohistochemistry and TUNEL analysis. Serum levels of proinflammatory cytokines were evaluated with cytometric bead array, measuring IL-1ß, TNF, IFN-γ, KC/CXCL1 and MCP-1. RESULTS: Intraarticular injection of the HA gel showed significantly reduced cartilage destruction and decreased osteophyte formation. Besides the biological and biomechanical effects of HA, we investigated lipid peroxidation products as an alternative inflammatory and potential mechanism contributing to OA. To address this, injection of the carbazate-modified component alone was performed, which also demonstrated a cartilage-saving effect. Besides the cartilage amelioration effects, decreased apoptosis, 4-hydroxynonenal (4-HNE) and MHC class II staining was recorded. No changes in serum levels of proinflammatory cytokines were detected. CONCLUSION: We have shown that the HA gel has an anti-destructive effect on articular cartilage (AC). Our results demonstrated that the carbazate-modified component could suppress apoptotic events, potentially by quenching of ROS/LPO products such as 4-HNE in OA joints. Modification of the HA molecule offers opportunities to introduce (covalent) coupling of additional molecules to the gel, with controlled retention and subsequent release in the joint.

A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides.

INTRODUCTION: Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA. METHODS: We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken. RESULTS: The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region. CONCLUSIONS: Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.

Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis.

OBJECTIVE: Findings from previous studies have suggested that subclinical inflammation of the synovium does not coincide with the appearance of rheumatoid arthritis (RA)-specific autoantibodies. This study was undertaken to examine the relationship between the presence of autoantibodies, changes in the synovium, and development of arthritis over time in a markedly larger, prospective study. METHODS: Fifty-five individuals who were IgM rheumatoid factor positive and/or anti-citrullinated protein antibody (ACPA) positive (detected by the anti-cyclic citrullinated peptide antibody test) and who were without any evidence of arthritis upon physical examination were included in the study. ACPAs were subsequently also detected using a multiplex chip-based assay. All individuals underwent magnetic resonance imaging and mini-arthroscopic synovial biopsy sampling of a knee joint at inclusion and were prospectively followed up. Proportional hazards regression analysis was performed to investigate whether changes in the synovium were associated with the onset of arthritis. RESULTS: Fifteen individuals (27%) developed arthritis after a median followup time of 13 months (interquartile range 6-27 months; range 1-47 months). No overt synovial inflammation was observed, but CD3+ T cell numbers in the biopsy tissue showed a borderline association with subsequent development of clinically manifest arthritis (hazard ratio 2.8, 95% confidence interval [95% CI] 0.9-9.1; P = 0.088). In addition, the presence of CD8+ T cells was associated with ACPA positivity (odds ratio [OR] 16.0, 95% CI 1.7-151.1) and with the total number of ACPAs present (OR 1.4, 95% CI 1.0-1.8). CONCLUSION: These findings confirm and extend previous results showing the absence of clearcut synovial inflammation in individuals having systemic autoimmunity associated with RA. However, subtle infiltration by synovial T cells may precede the signs and symptoms of arthritis in preclinical RA.

The influence of polygenic risk scores on heritability of anti-CCP level in RA.

The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA patients from three large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC) and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. GWAS-meta-analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a P-value of 2 × 10(-11) for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5 × 10(-8), and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r(2) in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a P-value of 3 × 10(-7). None of the known RA risk alleles (∼52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. In summary, anti-CCP level is a heritable trait, and HLA-DR3 and GP2 are associated with lower anti-CCP levels.

The HLA locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence.

OBJECTIVE: The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block. SUBJECTS AND DESIGN: Single nucleotide polymorphism (SNP) genotyping of individuals in the Swedish Congenital Heart Block (CHB) study population was performed. Low-resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases and 95 unaffected siblings). RESULTS: A case-control comparison between index cases and population-based out-of-study controls (n = 1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of P < 2.59 × 10(-6) (OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (P < 0.03 and P < 0.05, respectively), whilst HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (P < 0.04 and P < 0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (P < 0.02). CONCLUSIONS: HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, whilst DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time.

Regional differences regarding risk of developing rheumatoid arthritis in Stockholm County, Sweden: results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study.

OBJECTIVES: Rheumatoid arthritis (RA) is a complex disease that is associated with genetic and environmental factors. We have investigated geospatial variation in the risk of developing RA within Stockholm County, Sweden, with respect to established environmental risk factors for RA, as well as serologically defined subgroups of RA. METHOD: Information regarding geographical location for 1432 cases and 2529 controls from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, living in Stockholm County at RA symptom onset, or matched date for controls, was used to estimate geospatial variation in risk. We used generalized additive models (GAMs) to create a risk surface, calculate odds ratios (ORs), and adjust for potential confounding by smoking, education level, and RA within family. We performed a stratified analysis based on the presence/absence of anti-citrullinated peptide antibodies (ACPA). RESULTS: We found significant spatial variation in the odds of developing RA in Stockholm County. After adjustment for smoking, education level, and family history of RA, this geospatial variation remained. The stratified analysis showed areas with higher ORs for ACPA-positive RA and ACPA-negative RA, after adjusting for smoking, education level, and having a family history of RA. Living in the city of Stockholm was associated with decreased risk of RA. CONCLUSIONS: The risk of developing RA in Stockholm County is not distributed evenly and there are areas of increased risk that could not be explained by known factors. Further investigations of local exposures or social factors are warranted.

Genetic variation in the serotonin receptor gene affects immune responses in rheumatoid arthritis.

Many genetic variants associate with the risk of developing rheumatoid arthritis (RA); however, their functional roles are largely unknown. Here, we aimed to investigate whether the RA-associated serotonin receptor 2A (HTR2A) haplotype affects T-cell and monocyte functions. Patients with established RA (n=379) were genotyped for two single-nucleotide polymorphisms (SNPs) in the HTR2A locus, rs6314 and rs1328674, to define presence of the risk haplotype for each individual. Patients with and without the RA-associated TC haplotype were selected and T-cell and monocyte function was monitored following in vitro stimulations with staphylococcal enterotoxin B and lipopolysaccharide (LPS) using multiparameter flow cytometry. Within the cohort, 44 patients were heterozygous for the TC haplotype (11.6%) while none were homozygous. Upon stimulation, T cells from TC-carrier patients produced more proinflammatory cytokines (tumor necrosis factor alpha (TNF-α), interleukin-17 (IL-17) and interferon gamma (IFN-γ)) and monocytes produced higher levels of TNF-α compared with patients carrying the non-TC haplotype (P<0.05 and 0.01, respectively). Such cytokine production could be inhibited in the presence of the selective 5-HT2 receptor agonist (2,5-Dimethoxy-4-iodoamphetamine, DOI); interestingly, this effect was more pronounced in TC carriers. Our data demonstrate that association of RA with a distinct serotonin receptor haplotype has functional impact by affecting the immunological phenotype of T cells and monocytes.

Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies.

Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker-drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed.

Sick leave and disability pension before and after initiation of antirheumatic therapies in clinical practice.

OBJECTIVE: To investigate sick leave and disability pension in rheumatoid arthritis (RA) in relation to the initiation of biological and non-biological antirheumatic therapies in clinical practice. METHODS: Patients aged 19-60 years initiating non-biological mono (n=2796) or combination disease-modifying antirheumatic drug (DMARD) therapy (n=973), or biological agents (n=4787) were identified in the Swedish Rheumatology Quality Register between 1999 and 2007. Sick leave and disability pension data (1995-2010) were retrieved from national registers. RESULTS: During the year before the start of mono DMARD, combination DMARD and biological treatment, 10%, 12% and 43% of patients received disability pension benefits, respectively. The corresponding combined annual sick leave and disability pension days were 78 (54+25), 132 (105+27) and 190 (79+111). Irrespective of treatment type, initiators were characterised by a history of increasing sick leave and disability pension. Treatment start was associated with a break in this trajectory: sick leave decreased while disability pension increased, resulting in a net stabilisation of total days. Higher levels of days on sick leave and disability pension at treatment start were observed in patients initiating biologics in 1999 (236 days/year) compared with 2007 (150 days/year; p<0.001), but the trajectory thereafter remained largely similar and contrasted markedly with the level in the general population. CONCLUSION: Sick leave and disability pension increased rapidly before the initiation of antirheumatic therapy, which was associated with a halt but not a reversal of this development. Work ability is a metric of importance for clinical practice, signalling large remaining needs in the RA population, and the need for intervention earlier in the disease process.

Assessment of long-term safety and efficacy of etanercept in a 5-year extension study in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate long-term safety and efficacy of etanercept (ETN) in patients with rheumatoid arthritis (RA) without concomitant disease-modifying antirheumatic drug therapy. METHODS: A total of 549 patients enrolled in this 5-year, open-label extension after completing 1 of 2 randomised controlled studies; all patients received ETN 25 mg twice weekly during the extension. Safety assessments included physical exams, adverse events (AEs), vital signs, laboratory tests, and autoantibody evaluations. Key efficacy endpoints included numbers of responders achieving the American College of Rheumatology (ACR) criteria, low disease activity scores, and disease remission. RESULTS: Three hundred and eight (56%) patients completed the 5-year extension study. Total ETN exposure, including that received during the double-blind studies was 2212 patient-years. Withdrawals for efficacy- and safety-related reasons were 12% and 19%, respectively. The most common AE was upper respiratory infection (44%). Rates of serious infections decreased over the 5-year period; one case of suspected tuberculosis was reported. Rates of malignancies remained generally consistent during the 5-year period. There were no reports of demyelinating disease, serious blood dyscrasias, or opportunistic infections. The relationship between autoantibody titres and clinical events was not statistically significant. Less than 5% of patients tested positive for anti-etanercept antibodies and all antibodies were non-neutralising. After 5 years, ACR 20, 50, and 70 response rates were 78%, 51%, and 32%, respectively; the mean percentage of patients achieving low disease activity score (DAS ≤ 2.4) and remission (DAS ≤ 1.6) were 44% and 20%, respectively. CONCLUSIONS: ETN maintained a favourable safety profile and consistent efficacy throughout the 5-year study duration.

Generalisability of clinical registers used for drug safety and comparative effectiveness research: coverage of the Swedish Biologics Register.

OBJECTIVE: To determine coverage and generalisability of data in the Swedish Biologics Register ARTIS. METHODS: Patients with adult onset rheumatoid arthritis (RA) were identified in the National Patient Register and the Swedish Rheumatology Quality Register, including the ARTIS cohort of patients exposed to biological agents. Exposure to etanercept and adalimumab between 2006 and 2008 was determined by register linkage to the Prescribed Drug Register which contains patient-level data on >99% of all etanercept and adalimumab use in Sweden. RESULTS: Of 62 897 patients with RA, 6510 had received treatment with etanercept or adalimumab according to the Prescribed Drug Register. Of these, 5673 were also registered in ARTIS, resulting in a national coverage of 87%. The regional variation was small with >85% coverage in 18 of 21 counties. In multivariable analysis, ARTIS-registered and non-registered patients did not differ by age (p=0.62), sex (p=0.84) or education level (p=0.24). CONCLUSION: Nationwide drug dispensing and demographic data may function as quality metrics for coverage and generalisability assessments. Using such data, the coverage of ARTIS was estimated at 87% with no indications of compromised external generalisability regarding demography.

Small-area variations in sales of TNF inhibitors in Sweden between 2000 and 2009.

OBJECTIVE: To measure small-area variations in sales per capita of tumour necrosis factor (TNF) inhibitors. METHODS: For 2000-2009, sales data on etanercept, infliximab, and adalimumab were retrieved from the Swedish National Corporation of Pharmacies, which keeps data on drugs dispensed in ambulatory care and hospitals. As points of reference, data were retrieved on all drugs, non-biologic treatments for chronic inflammatory disorders (sulfasalazine, methotrexate, azathioprine), and for a biologic used in a different therapeutic area (trastuzumab). As a corollary measure to sales per capita, penetration of biologics in the rheumatoid arthritis (RA) population was calculated using nationwide registers. Small areas were defined as the 21 counties of Sweden. RESULTS: From 2000 to 2009, annual TNF inhibitor sales increased 9-fold from 195 to 1779 million SEK (0.7-5.0% of total drug expenditure). The county variation in sales per capita, initially 6.2-fold (coefficient of variation 42%), decreased to 2.3-fold in 2009 (24%). During the same period, total drug expenditure per capita remained at a 1.2-fold county variation (4-6%). Sales per capita variations of non-biologic treatments against chronic inflammatory diseases ranged from 1.5 to 1.8 (12-16%). For trastuzumab, a 3.2-fold variation (30%) was observed in 2009. At the patient level, there was a 2-fold county variation (from 10% to 21%) in biologic penetration in RA. County-specific sales per capita were associated with mean RA duration (r = -0.52, p = 0.015) and C-reactive protein at treatment initiation (r = -0.49, p = 0.025), while pain was borderline significant (r = -0.43, p = 0.055). CONCLUSIONS: Despite universal access to treatment, substantial but decreasing small-area variations were observed. Although geographic variations are anticipated initially, their persistence calls for investigation of patient equity and treatment appropriateness as counties seem to have different initiation thresholds.